Wolters Kluwer Health
may email you for journal alerts and information, but is committed
to maintaining your privacy and will not share your personal information without
your express consent. For more information, please refer to our Privacy Policy.

Objective: To identify risk factors for stillbirth in developing countries and to measure their impact by calculating the population attributable fraction (PAF) for each risk factor.

Study Design: Systematic review of published studies on risk factors for stillbirth within 3 broadly defined categories: infections, other clinical conditions, and context-dependent conditions such as socioeconomic status, maternal literacy, and receipt of antenatal care. Where statistically significant associations were found between a risk factor and occurrence of stillbirth, the PAF (the proportion of cases occurring in the total population that would be avoided if the exposure was removed) was calculated.

Results: A total of 33 studies, conducted in 31 developing countries, were included in the review. The definition of stillbirth varied widely in these studies. Risk factors for stillbirth having a PAF higher than 50% were maternal syphilis, chorioamnionitis, maternal malnutrition, lack of antenatal care, and maternal socioeconomic disadvantage.

Conclusions: Maternal syphilis prevention, screening and treatment together with other interventions targeting universal use of antenatal care (that includes screening for syphilis) and improving the socioeconomic conditions including nutritional status of the mother, could effectively contribute towards reducing the unacceptably high burden due to stillbirth in developing countries.

This systematic review shows that risk factors with high impact on stillbirth in developing countries are maternal syphilis, chorioamnionitis, maternal malnutrition, lack of antenatal care, and maternal socioeconomic disadvantage.

From the *Centre for the Evaluation of Effectiveness of Health Care-CeVEAS, Azienda USL di Modena, Viale Muratori, Modena, Italy; Departments of †Reproductive Health and Research and ‡Making Pregnancy Safer, World Health Organization, Geneva, Switzerland

The authors are indebted to Dr. Carlo Gagliotti for the statistical support, to Dr. Paul FA Van Look, Dr. Nathalie Broutet, and Dr. Vittorio Basevi for their comments, and Jitendra Khanna for assisting with the editing of the paper. UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research (HRP), funded the study.

STILLBIRTH IS BOTH A medical and lay term for a fetus that is born dead. The World Health Organization’s (WHO) International Classification of Diseases (ICD-10)1 defines stillbirth (fetal death) as “death before the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of pregnancy, which is indicated by the fact that after such separation, the fetus does not show any evidence of life.”

In ICD-10, stillbirth is included under the term “perinatal mortality,” which combines fetal death (death of a fetus after 22 completed weeks [154 days] of gestation or death of a fetus with a birth weight of 500 g) and newborn (death within 7 completed days after birth). WHO recommends that where possible all fetuses and infants weighing at least 500 g at birth, whether born alive or dead, should be included in national perinatal mortality statistics. However, for international comparison of perinatal mortality data, ICD-10 recommends the use of the following definition of fetal death: death of a fetus weighing at least 1000 g occurring after 28 completed weeks of gestation or at having at least 35 cm body length.1

Clearly, these definitions are difficult to apply in the collection of data on perinatal death. This is illustrated by the great disparity between definitions used in different data sources, particularly in countries without an established vital registration system. Underreporting, particularly of stillbirths, and misclassification of perinatal deaths are common problems. To reduce the confusion created by multiple definitions of perinatal mortality and to improve understanding about the health burden of stillbirths, separate counting of stillbirths and early neonatal deaths has been advocated.2,3 Such a practice would help to better inform policies and programs aimed at reducing stillbirths.

WHO estimates that worldwide 3.3 million stillbirths occur each year, accounting for over half of all perinatal deaths.4,5 The majority of these deaths take place in developing countries. While countries in South-East Asia report the highest overall numbers of stillbirths, countries in Africa have the highest incidence rates per 1000 live births.4 In high-income countries stillbirth rates are as low as 6 per 1000 live births, whereas in less developed countries they can be as high as 26 per 1000 live births.4 Stillbirth rates also vary within countries, being higher in economically poorer communities compared with the economically well-off populations.2

One third to one fourth of all stillbirths are estimated to take place during delivery.3,4 The remaining proportion of stillbirths is estimated to occur before delivery, and these stillbirths are due to a variety of factors of maternal and fetal origin, including infections and environmental hazards which may affect maternal health during pregnancy and fetal development and survival. In settings where women receive appropriate care during childbirth, intrapartum deaths represent less than 10% of stillbirths and are mainly due to unexpected complications.4 This suggests that stillbirths are closely linked to the use and quality of maternal services: higher stillbirth rates in socioeconomically disadvantaged populations may be a reflection of the absence or poor quality of care women receive during pregnancy and delivery. Hence, stillbirth rate could be an indicator of access to, and quality of, maternal health services. It is also regarded as a development indicator.2

Even though stillbirths represent a large proportion of perinatal deaths, direct and indirect causes of stillbirths are poorly understood, particularly in developing countries. One previously published systematic review reporting causes and risk factors for stillbirth included only studies conducted in developed countries,6 while 3 other reviews,2,3,5 which included studies from both developed and developing countries, were focused on prevalence estimates and did not investigate risk factors for stillbirth. This systematic review aims to estimate for the first time the main risk factors for stillbirth in developing countries and to measure their impact in terms of population attributable fraction (PAF).

Methods

Search Strategy and Identification of Studies

Systematic literature searches were performed on electronic databases of Medline, EMBASE, LILACS, and IMEMR. Thesaurus terms for each of the databases, together with free text, were used for the following terms: stillbirth, fetal death, risk factors, cause of death, case–control studies, cohort studies. The search was limited to articles on human subjects and to those published from 1996 to present. The decision regarding the time frame was taken arbitrarily and aimed to identify more recent data. Such data might be more reliable,7–9 first because more recent data are supposed to be better collected and second because the prevalence of a single risk factor can change due to time trend. There were no language restrictions in the search. One author initially evaluated titles and abstracts of the identified citations for potential inclusion in the review. Studies conducted in developed countries and those that did not report data on stillbirth or adverse pregnancy outcomes were excluded. The development status of a country was based on United Nations classification.10 In case of doubt the full text of the article was considered for inclusion. Full-text articles of the citations deemed relevant at this stage were assessed for final inclusion.

Studies were eligible for inclusion if the full text was available, if more than 10 cases of stillbirth were reported, and if data to construct contingency tables with the explanatory variables and the outcome were presented. Any definition of stillbirth was considered. In case in which a study appeared in more than 1 publication, all the publications were included, provided the different publications reported on different subsets of data. Otherwise, the article reporting the largest data set was included. Additional search including review of reference lists of key papers was performed. Finally, relevant papers known by the researchers were incorporated if they fulfilled the inclusion criteria.

Data Extraction and Presentation

A data extraction instrument specifically developed for this review was used to collect information on: (1) study variables; (2) risk factor assessed; (3) measures of association; and (4) definition of stillbirth. Risk factors studied were considered within 3 broad categories to facilitate interpretation for potential programmatic implications: infections, other clinical conditions and context-dependent conditions. Context-dependent conditions examined in primary studies included nonclinical factors that are usually cited as associated with stillbirth, such as socioeconomic status, maternal literacy and receipt of antenatal care. Findings were presented in separate tables according to these broad groupings. If a study had analyzed risk factors relevant to more than 1 group, it was presented in all pertinent tables.

When a statistically significant risk factor for stillbirth was identified in a study, PAF, i.e., the proportion of cases of disease (in our case the proportion of cases of stillbirth) occurring in the total population that would be avoided if the exposure was removed, was calculated whenever possible. To calculate PAF, the included studies were classified and analyzed as cohort or case–control with respect to stillbirth, regardless of the original study design. For example, if a case–control study of a condition other than stillbirth (e.g., eclampsia) reported stillbirth among the outcomes for cases and controls, these were treated as cohorts of exposed (i.e., eclampsia cases) and unexposed (i.e., control group) mothers. Two different formulas were employed to calculate PAF. The Levin formula was used for cohort studies presenting a crude measure of association,11 while the Miettinen formula12 was used for case–control studies and cohort studies where the estimate of the association was adjusted for confounding.13 In the case of cohort studies with exposed and unexposed sampled separately, PAF was calculated only when the authors provided an estimate of the proportion of exposed in the study population or an estimate of the proportion of cases coming from the exposed group. Accordingly with the available literature, confidence intervals were calculated whenever possible.14,15

Results

Overall, 650 papers were identified through electronic searches and 18 through reference lists. Of these, 106 were judged to be relevant on the basis of their titles and abstracts. Of these only 82 were assessed because full text for 24 papers could not be found. Forty-nine articles were excluded on the basis of the above-mentioned exclusion criteria. A total of 33 studies, conducted in 31 different countries, were finally included in the review16–48: 13 were cohort studies,16–28 5 case–control studies analyzed as cohort studies,29–33 and 15 were case–control studies.34–48 Twenty-eight studies were hospital-based, while 5 had been conducted in the community. The definition of stillbirth varied among the studies: They had defined stillbirth according to either gestational age (varied from 20–28 weeks of gestation) or birth weight (varied from 350 g to more than 1000 g). Thirteen studies included no definition of stillbirth. Another 13 had excluded women with multiple pregnancies from the study sample, while 7 had excluded stillbirth with congenital malformations. Three studies reported performing post mortem examination on the fetus and none reported performing any kind of verbal autopsy. Two studies reported the proportion of macerated stillbirths, while the others did not specify this aspect.

Table 1 shows studies that analyzed the association between infections in the mother or the fetus and stillbirth. Reported infections included syphilis, HIV, and malaria. Maternal syphilis assessed in 7 studies (6 cohorts) was consistently found to be significantly associated with stillbirth with PAF ranging from around 2% to more than 80%.16–20,28,34 HIV and malaria infection in the mother, assessed in fewer studies,21,33,34 had a less defined role in the origin of stillbirth with maternal HIV never reaching statistical significance and maternal malaria being significantly associated with stillbirth only in 1 study conducted in an area of unstable transmission. Other infections studied included chorioamnionitis and fetal bacteremia. Chorioamnionitis was assessed in 3 case–control studies, which reported PAF ranging from 45% to 89%.35–37 Fetal bacteremia was of concern in a single case–control study for which PAF could not be calculated due to zero exposure among the control group.38

Studies that analyzed the association between clinical risk factors other than infections and stillbirth are summarized in Table 2.22–26,28–32,34,40,43–48 Among the significantly associated factors were maternal complications during pregnancy and delivery such as pre-eclampsia, diabetes, anemia, obstructed labor, or previous stillbirth or neonatal death. Maternal malnutrition, assessed in 3 studies (1 cohort), was reported to be significantly associated with stillbirth, with PAF ranging from 8% to 70%.23,34,45 Maternal obesity and low birth weight, assessed in 5 studies (2 cohorts), appeared to be critical risk factors for stillbirth in some studies,22,44,47 while in others these factors were less marked.28,46

Table 3 refers to studies that attempted to quantify the impact on stillbirth of risk factors that were defined in this review as context-dependent. Among the contextual influences studied, lack of antenatal care appeared to have high impact on stillbirth in 5 studies (2 cohorts), with a PAF of around 16% to more than 70%.27,28,43–45 Socioeconomic disadvantage, taken as low income and maternal illiteracy assessed in 3 studies, all case–control, had also a significant association with stillbirth. PAF for these risk factors varied from 2% to more than 75%.45–47

Discussion

This systematic review of the literature identified risk factors for stillbirth in developing countries and estimated the proportion of stillbirths that would be prevented if a particular risk factor is eliminated in a range of study settings.

Main Findings

Five risk factors (maternal syphilis, chorioamnionitis, maternal malnutrition, lack of antenatal care, and maternal socioeconomic disadvantage) were found to be significantly associated with stillbirth (with a PAF greater than 50%) in more than 1 study.

These findings can be categorized into 2 broad groups. The first group are context-dependent risk factors,27,28,43–47 such as maternal illiteracy, not receiving antenatal care, or socioeconomic disadvantage, i.e., risk factors for which a direct association to the outcome is not clear. The second group of risk factors relates to clinical conditions (maternal or fetal infections in particular) for which a causal pathway to the final outcome is already known or suspected,49 such as maternal syphilis16–20,28,34 or chorioamnionitis.35–37

Interpretation of the Findings

It is possible that the contextual factors (the first group of risk factors) may not be the actual risk factors for stillbirth. However, they could be proxy factors for as yet unknown risks and could serve as useful indicators in specific populations. It is conceivable that providing accessible health-care services, especially to disadvantaged women, can lower stillbirth rates, irrespective of the actual cause, as is already seen in the case of infant mortality.50

For some of the specific clinical conditions identified as significant risk factors (second group of risk factors), on the other hand, cost-effective interventions to directly reduce the impact are already available. For example, antenatal syphilis screening with on-site testing and immediate treatment was shown to be cost-effective and reported to be beneficial in reducing not only the occurrence of stillbirth but also the burden of disease resulting from congenital syphilis.51 Routine incorporation of this intervention in antenatal care programs in developing countries could significantly reduce stillbirth rates in these settings. Indeed, the above-reported association of receipt of antenatal care with lower stillbirth rates might be partly due to provision of antenatal syphilis screening as part of antenatal care.

The PAF values calculated in this review for each risk factor varied widely in different settings. For example, for maternal syphilis the PAF ranged from 1.85% (95%CI 1.65–2.02) in a multicenter study in South America28 to 81.6% (95%CI 59.3–92.1) in the Russian Federation.16 One explanation for this large variation is that PAF depends not only on the rate ratio but also on the prevalence of exposure in a given context. Thus, it is quite plausible that elimination of syphilis (which in recent years has reemerged in former USSR countries),49 would have a larger impact in the Russian Federation than in countries where prevalence of syphilis is low. On the other hand, it is also possible that the variation is a reflection of the poor quality of studies such that inaccuracy in the estimation of the stillbirth rate is affecting the PAF calculation.2,52 In the case of certain studies it was not easy to use and interpret data, either because the data presented in tables were discordant with those presented in the text, or there were errors in data analysis25,37,38,44 (e.g., matched case–control studies analyzed as unmatched ones).

The reason for including studies found to be problematic was simply that data on this topic from developing countries are so scarce. Yet, it was to some extent reassuring that in relationship to maternal syphilis, chorioamnionitis, not receiving antenatal care, maternal malnutrition, and socioeconomic disadvantage there was a degree of concordance among the studies. Thus while the PAF values need to be interpreted with caution, they nonetheless can be considered as indicative of the actual risks.

Another consideration when interpreting PAF is that it indicates the proportion of stillbirths that could be avoided in case an intervention able to reduce immediately that particular exposure to zero could be implemented, while all other variables remain constant. For example, if PAF for stillbirth due to maternal syphilis is 80% in a given setting, by using the syphilis screening and treatment program in pregnant women53 the rate of maternal syphilis can be reduced to zero, and stillbirth rate could be reduced by 80% if other changes do not occur. This implies that resources to implement syphilis screening and treatment should not be diverted from other preventive programs (for example, immunization or delivery care) otherwise the amount of stillbirth reduction will diminish accordingly.

Definitions and Potential Underestimation of Stillbirth

As already pointed out earlier, 5,49 there was a wide variation in the definition of stillbirth in the studies included in the review. This is partly due to different definitions of stillbirth used in different countries and to the definitions changing over time.5,54 Many studies did not report separate data for stillbirths and neonatal deaths. Twenty percent of the excluded studies were rejected for this reason. Many experts believe that stillbirth rates are grossly underestimated all over the world and that there is a risk of misclassification of stillbirth with neonatal death not only in developing countries5,6,54 but also in developed countries.6,55,56 Stillbirths are being underestimated not only because they are not counted at all5,57 but also because stillbirth rates calculated from observational studies are frequently underestimates.52 Measurement of more accurate prevalence rates of stillbirths and associated risk factors and causes in developing countries should be a priority.

Strengths and Potential Limitations

To our knowledge this is the first attempt to systematically review the literature providing data on this topic from developing countries settings, and to provide estimations of PAF. The review employed a comprehensive search strategy, that involved databases including studies from developing countries like LILACS and IMEMR irrespective of the language, thus increasing the chance of retrieving all relevant studies conducted in developing countries. The estimations of PAF, which measure the contribution of a particular exposure to the overall rate of disease in a given population, provide valuable messages to policy makers for priority setting in a specific country or region and therefore could significantly improve the health of women and children.

One limitation of this review is the considerable number of studies that could not be retrieved in full text (n = 24). Another limitation is the difficulty in interpreting PAF. As explained above, PAF estimates change in settings with different prevalence of exposure. Therefore, the results of a single study are not automatically applicable to different contexts. Second, the right interpretation of PAF depends on the quality of the study assessed; low-quality studies that provide invalid estimates of association will lead to invalid estimates of PAF.

Implications for Policy

Despite the lack of good-quality studies on stillbirths in developing countries, this review provides indications about important risk factors of stillbirths in those countries. Maternal syphilis, lack of appropriate antenatal care for all women, and socioeconomic disadvantage stand out as key risk factors in developing countries. Strengthening health services, including antenatal care services that comprise screening for syphilis, would help to alleviate the burden of ill health from stillbirths in developing countries.

Implications for Research

Data on stillbirths from developing countries are scarce and often not reliable, and, as for many other public health conditions, the “inverse information and care law” is valid: “The communities with the most fetal deaths have the least information on these deaths and least access to cost-effective interventions to prevent them.”57 Better-quality research as well as more reliable estimates of stillbirths for each country is therefore needed. A greater amount of good-quality data translated into PAF would be valuable to guide the setting of priorities in public health programs in developing countries.

55. Maternal and Child Health Research Consortium, London. Confidential enquiry into stillbirth and death in infancy (CESDI), 8th Annual Report, 2000. Available at http://www.cesdi.org.uk/CESDIpublication.htm. Accessed July 12, 2006.